Prescribing Information for Isotretinoin

Oral isotretinoin has revolutionized the treatment of severe acne. It is the only drug that can achieve a sustained effect, even at low doses. There are a variety of side effects. However, many of these occur infrequently and can be reduced by dose reduction (with extended treatment duration). The most important risks are discussed in more detail in the following article. The adverse effects are negatively overshadowed by the proven teratogenicity of the substance.

Oral isotretinoin is not a “wellness” medication. The indication must be correct (there are several differential diagnoses!) and the patients must be well informed about the side effects. In the following article, only orally administered isotretinoin is discussed. Isotretinoin sparks its action on all pathogenetically important mechanisms of acne development. In particular, the drug has an impressive effect on highly inflamed forms of acne. Isotretinoin (13-cis-retinoic acid), which was introduced in Switzerland in 1983 under the brand name ^Roaccutan®, is a natural metabolite of vitamin A and retinoic acid. Within two to six hours after ingestion, the substance is absorbed. The half-life is 7-37 hours and 11-50 hours for their metabolites. The substance crosses the plant barrier, is broken down by the liver and excreted through faeces and urine. The bioavailability is 25%. It can be greatly improved when isotretinoin is taken with a high-fat diet because of the lipophilicity of the substance. After discontinuation of treatment, elevated levels of isotretinoin and its metabolites are no longer detected in serum after two to four weeks [1].

Unfortunately, this effective drug has several side effects that limit its use.

Indication

The treatment of acne is specified in guidelines from various national societies [2, 3]. The indications for the treatment of acne are “fluid”. As a rule, acne is treated when there is discomfort or when permanent damage such as scarring is to be expected. Isotretinoin has a limitatio and may only be used for severe and therapy-resistant forms of acne (see the FOPH’s list of specialties [4]). Therapy resistance occurs when local acne therapeutics, which have proven efficacy, have been used unsuccessfully for at least three months. Practical experience shows that often local treatment attempts are discontinued too early due to false expectations, improper applications or irritant effects. However, with proper instruction and controls, this shortcoming can be minimized.
Acne is not only a cosmetic problem, but can also have substantial influences on psychological well-being, independent of objective clinical expression [5]. An extreme situation is dysmorphic acne. It is characterized by an extreme discrepancy between objective findings and subjective perception. It is important not to trivialize this problem, because in addition to severe psychological distress, the risk of suicide is also increased [6]. This type of dysmorphophobia may also be an indication for isotretinoin.

Dosage

The classic dosage, as also stated in the package insert, is 0.5-1.0 mg/kgKG daily. For a 60 kg person, this would be 30-60 mg daily. Plewig showed that even low to very low doses have very good effects on inflamed and non-inflamed acne lesions. He found that doses around 0.15 mg/kgKG sparked an effect almost as good as the classic higher dose of 0.5 mg/kgKG, if treated long enough [7]. The major advantage of the lower doses is the strong reduction of dose-related side effects. There is also experience that a flare-up of acne can be avoided with a lower dose.

The initial intensification of acne can be very unpleasant and, in extreme cases, can lead to acne fulminans, which is treated with internal corticosteroids. Certain authors therefore recommend starting treatment with a lower dose [8].

As a rule, patients have to expect a therapy duration of four to six months. Isotretinoin is the only drug that exerts a lasting effect on acne. Whether this sustainability is related to total cumulative dose has not been conclusively demonstrated. Several studies showed that the recurrence rate can be significantly reduced if a cumulative dose of 100-120 mg/kgKG is targeted (for summary see [9]). A cumulative dose higher than 120 mg/kgKG provides no additional benefit. However, it should be noted that there are also studies that doubt this approach [10, 11].

Especially in milder forms of acne, symptoms may disappear long before the cumulative dose is reached. If one then wanted to reach the recommended cumulative dose, one would have to treat asymptomatic patients for weeks with a drug that has potential side effects.

Side effects

A large number of side effects are described. However, some are observed only very rarely and therefore their significance is unclear (coincidence or causality?). In the following, only the most important and most frequent side effects will be discussed. Further information is available in the literature [9, 12]. In essence, the side effects of isotretinoin are those of vitamin A. Any unwanted effects are outshone by the teratogenicity of the substance.

The most significant and common side effects: Teratogenicity, dry and cracked lips, dry eyes, dry skin, UV erythema, nosebleeds, headaches, hair loss, increase in triglycerides, decrease in high density lipoproteins, hypercholinesterinemia, hepatitis, pancreatitis (due to increased lipids), bacterial infections (e.g., with staphylococci in dehydration of skin and eyes), benign intracranial hypertension, night blindness, myopathy (especially during strenuous exercise).(e.g., with staphylococci in the case of desiccation of the skin and eyes), benign intracranial hypertension, night blindness, myopathy (especially with heavy physical exertion), bone changes (with therapy duration of more than one year).

Teratogenicity: Shortly after the introduction of isotretinoin, congenital malformations were observed in children born to mothers who took isotretinoin during pregnancy. The relative risk of developing retinoid embryopathy is approximately 26% and is comparable to the risk of thalidomide. Observed malformations of various organs such as face, eyes, ears, skull, CNS, cardiovascular system, thymus and parathyroid [13]. Therefore, women of childbearing age must practice safe anticonception one month before, during, and one month after completion of treatment, regardless of whether they have sexual intercourse. Crjins et al. published a review on this topic and summarized the European studies. 0.2-1 patients per 1000 patients consumed isotretinoin during pregnancy, with associated consequences. The authors also noted that pregnancy prevention programs are generally inadequate. This is where prescribing physicians are challenged. Isotretinoin should be prescribed only to individuals whose compliance is good and in whom safe anticonception is assured. It is also strongly recommended that patients sign an “informed consent” form. This form, on which all important side effects are noted, can be obtained from any company that sells isotretinoin. In the case of minor patients, it is advisable to also inform the parents and have them sign. Regular pregnancy tests are also recommended. Above all, pregnancy should be ruled out before starting treatment.

Suicidality and depression: As early as the 1980s, the first case reports were published suggesting an association of isotretinoin with depression and suicidality. Because good studies were lacking, the regulatory authorities required appropriate warnings in the package leaflets. In the meantime, there are many and extensive studies showing that the risk of suicide and mental abnormalities is not higher with isotretinoin therapy compared with a control group in the same age category (for review, see [14]). This discussion must also take into account that acne can have multiple negative effects on the psyche. There is also evidence that emotional stress factors may play a role in the pathogenesis of acne [15]. In these cases, one must ask whether it is not the therapy but a pre-existing psychological stress or the acne itself that explains the emotional changes. Nevertheless, the author of this article has the impression that there are individual cases in which isotretinoin exerts a negative influence on the psyche. It is therefore advisable to discuss this problem at the time of prescription as well.

Inflammatory bowel disease: A similar discussion is ongoing regarding the association of isotretinoin with inflammatory bowel disease. Both entities, acne and inflammatory bowel disease, occur in the same age group. Ali Alikhan evaluated this issue [16] and concludes that the absolute risk is very small and there are no evidential studies showing a causal relationship.

Dry skin and mucous membrane: Virtually all patients taking a dose of 0.5 mg/kgKG suffer from cheilitis. If this is not present, regular intake must be doubted. As a rule, the motivation for therapy is very good, which is why this side effect is usually tolerated without problems, especially if the lips are greased regularly.

Eye problems: In the eye area, quite a few side effects are discussed, such as abnormal secretion of Meibomian glands, blepharoconjunctivitis, dry eyes, blurred vision, decreased dark adaptation, and intolerance to contact lenses. These side effects are of relevance especially at high doses (>0.5 mg/kgKG) [17]. For contact lens wearers, wearing glasses, lower doses, regular moistening and/or ophthalmologic checks are recommended during therapy.

Control of blood lipids and transaminases: Minor elevations of blood lipids are encountered relatively frequently. If they are strongly elevated, measures are urgently required (reduction of the dose or discontinuation of therapy, dietary measures). Liver enzymes should also be monitored because of the risk of hepatitis. Mild elevations are common. They usually normalize spontaneously with therapy or with dose reduction. Laboratory controls of triglycerides, cholesterol, and liver enzymes should be performed before and one month after treatment. With normal values during treatment, the risk of abnormalities during a subsequent treatment period is low [18].

Isotretinoin in athletes: muscle soreness-like complaints occur relatively often. Creatine kinase elevation is common in this setting and is a benign phenomenon [19]. Creatine kinase and myoglobin should be monitored, as well as renal function, in cases of severe exercise, severe myalgias, and arthralgias, as rare cases of rhabdomyolysis have been described.
Interactions: Additional topical acne therapy is not recommended as there is no additional benefit and this leads to additional skin irritation. Additional doses of vitamin A also increase the risk of side effects. In general, due to the increased irritability of the skin, all irritating procedures should be avoided (peelings, depilations, etc.). The concomitant administration of tetracyclines is contraindicated because of the risk of increased intracranial pressure.

Martin Pletscher, MD

Literature:

1. Ganceviciene R, Zouboulis CC: Isotretinoin: State of the Art Treatment for Acne Vulgaris. Journal of the German Dermatological Society 2010; 8: S47-S59. doi:10.1111/j.1610-0387.2009.07238.x.
2. 013-017l_S2k_Behandlung_der_Akne_2011-10-Korr1 – 013-017l_S2k_Behandlung_der_Akne_2011-10-Korrektur.pdf: www.awmf.org/uploads/tx_szleitlinien/013-017l_S2k_Behandlung_der_Akne_2011-10-Korrektur.pdf (July 2013).
3. Current Guidelines and Guidelines in Development Aad.org: www.aad.org/education/clinical-guidelines/current-and-upcoming-guidelines (July 2013).
4. Bundesamt Für Gesundheit – Spezialitätenliste (SL): www.bag.admin.ch/themen/krankenversicherung/00263/00264/00265/index.html?lang=de (August 2013).
5. Barnes LE, et al: Quality of life measures for acne patients. Dermatologic Clinics 2012; 30: 293-300. doi:10.1016/j.det.2011.11.001.
6. Bowe WP, et al: Body Dysmorphic Disorder Symptoms Among Patients with Acne Vulgaris. Journal of the American Academy of Dermatology 2007; 57: 222-230. doi:10.1016/j.jaad.2007.03.030.
7. Plewig G, et al: Low Dose Isotretinoin Combined with Tretinoin Is Effective to Correct Abnormalities of Acne. Journal of the German Dermatological Society 2004; 2: 31-45. doi:10.1046/j.1439-0353.2004.03739.x.
8. DRM870.indd – 182270: www.karger.com/Article/Pdf/182270 (September 2013).
9. thielitz A, Gollnick H: Isotretinoin. Der Hautarzt 2013; 64: 263-268. doi:10.1007/s00105-012-2467-z.
10. Quéreux G, et al: Prospective Study of Risk Factors of Relapse after Treatment of Acne with Oral Isotretinoin.  Dermatology 2006; 212: 168-176. doi:10.1159/000090658.
11. Borghi A, et al: Low-cumulative Dose Isotretinoin Treatment in Mild-to-moderate Acne: Efficacy in Achieving Stable Remission. Journal of the European Academy of Dermatology and Venereology 2011; 25: 1094-1098. doi:10.1111/j.1468-3083.2010.03933.x.
12. McLane J: Analysis of Common Side Effects of Isotretinoin. Journal of the American Academy of Dermatology 2001; 45: S188-S194. doi:10.1067/mjd.2001.113719.
13. Lammer EJ, et al: Retinoic acid embryopathy. New England Journal of Medicine 1985; 313: 837-841. doi:10.1056/NEJM198510033131401.
14. Sundstrom A, et al: Association of Suicide Attempts with Acne and Treatment with Isotretinoin: Retrospective Swedish Cohort Study. BMJ 2010; 341: c5812-c5812. doi:10.1136/bmj.c5812.
15. Niemeier V, Kupfer J, Gieler U, Acne vulgaris – psychosomatic aspects. Journal of the German Dermatological Society 2010; 8: S95-S104. doi:10.1111/j.1610-0387.2006.06110_suppx.x.
16. Alikhan A, et al: Acne Treatment and Inflammatory Bowel Disease: What Is the Evidence? Journal of the American Academy of Dermatology 2011; 65: 650-654. doi:10.1016/j.jaad.2011.04.016.
17. Cumurcu T, et al: Comparison of Dose-related Ocular Side Effects During Systemic Isotretinoin Administration. European Journal of Ophthalmology 2009;19(2): 196-200.
18. Accutane Official FDA Information, Side Effects and Uses: www.drugs.com/pro/accutane.html> (September 2013).
19. Kaymak Y: Creatine Phosphokinase Values During Isotretinoin Treatment for Acne. International Journal of Dermatology 2008; 47: 398-401. doi:10.1111/j.1365-4632.2008.03491.x.

CONCLUSION FOR PRACTICE

• Isotretinoin acts against all pathogenetically important mechanisms of acne development.
• The indication of isotretinoin must be correct and the patient must be well informed about the side effects.
• Isotretinoin may only be used in severe and therapy-resistant forms of acne (local acne therapeutics used unsuccessfully for at least three months).
• The classical dosage is 0.5 mg/kgKG daily.
• The most common side effects: Teratogenicity, dry and cracked lips, dry eyes, dry skin, UV erythema, nosebleeds, headaches, increase in triglycerides, decrease in “high density” lipoproteins, hypercholinesterinemia, bacterial infections.

Dermatology Practice 2014; 24(1): 18-21